Memory and awareness during anaesthesia
London, UK
* E-mail: zeponte{at}yahoo.co.uk
Editor—I could not help noticing that not a single word can be found about the role of neuromuscular blockers in awareness under anaesthesia in either the editorial1 or in the abstracts of the 7th International Symposium on Memory and Awareness in Anaesthesia published in the June issue of the journal.2 Predictably, little progress has been made in the last 10 yr in tackling the problem of awareness under anaesthesia and skeletal muscle movement continues to be the ‘gold standard’ for detection of this embarrassing complication. However, it is apparent from what appears in the literature that the opinion formers and possibly those providing the specialist training have largely ignored many attempts, including mine in 1995,3 to alert the profession for the misuse of neuromuscular blockers. Perhaps, there is a positive side to the persistence in practice of this avoidable complication: it provides a powerful stimulus for the research into the mechanisms of anaesthesia and memory formation.
Rotherham, UK
* E-mail: glynch{at}doctors.org.uk
Editor—We read with interest the editorial by Sneyd and Mathews1 and in particular their comments on the recent B-Unaware trial and the use of nitrous oxide. Although we agree with their assertion that ‘the additivity of MAC fractions of nitrous oxide and inhalation agents for the suppression of reflex responses is well recognized, their interaction on memory formation is less clear and cannot be assumed to be additive’, the information from the B-Unaware trial suggests that the interaction of nitrous oxide and volatile, if anything, may have a more than additive effect on memory.4 It is striking that none of the patients in the ‘definite’ or ‘possible’ awareness groups in B-Unaware was treated with nitrous oxide. Indeed, one possible message from this trial might be that the use of a BIS- or end-tidal anaesthetic gas (ETAG)-guided volatile protocol in combination with nitrous oxide could reduce the incidence of awareness in (relatively) high-risk patients to zero! This finding is in contrast to those of Myles and colleagues5 in the ENIGMA trial, which showed a non-significant trend towards increased awareness in the nitrous oxide-treated group. This finding from B-Unaware may be hypothesis-generating for future trials examining awareness using volatile with or without nitrous oxide.
London, UK
* E-mail: andrew.morley{at}gstt.nhs.uk
Editor—In their editorial, Sneyd and Mathews1 state ‘The investigators [B-Unaware trial]4 have shown that both awareness risk-reduction strategies, BIS monitoring, or care by anaesthetic protocol, work equally well ... ’. In doing so, they effectively draw two conclusions from that trial, both of which are unsupportable after close scrutiny of the experimental methodology. The first conclusion, one reached neither by the investigators themselves nor in the editorial accompanying their paper,6 is that the overall incidence of awareness in the study patients was lower than it would have been had the two strategies not been used. The observed incidence was 0.21%, similar to that seen in other studies of the general population.7 8
Sneyd and Mathews assume a ‘real’ incidence of awareness of 1% in the B-Unaware patients—an assumption shared, at least initially, by the trial investigators. This expectation is ill-founded. According to the investigators, it is based on two trials relating specifically to anaesthesia for cardiac surgery—in which 3/2049 and 8/70010 patients, respectively, reported awareness—together with the incidence observed in unmonitored patients in the B-Aware trial, namely 11/1238.11 The proportion of patients in the B-Unaware trial undergoing any type of heart surgery is not reported, but many of the patients were recruited according to the criteria not used in the B-Aware trial, including daily alcohol consumption, ASA class IV–V, and marginal exercise tolerance, respectively, accounting for 18%, 22%, and 38% of all patients.
There is good reason to suppose that these new B-Unaware criteria for high awareness risk are much less stringent than those in the B-Aware trial. Although chronic alcoholism has been shown to increase anaesthetic requirements,12 the effects of daily alcohol consumption are unknown. In their study of 19 575 patients, Sebel and colleagues7 used multiple regression to determine that ASA class III–V patients were more at risk of awareness than ASA I–II patients (OR 2.85; 95% CI 1.29–6.28). However, of the 25 patients reporting awareness, 12 were ASA class III (out of 5093 ASA III patients) and two were class IV or V patients (out of 880). Had the authors restricted their analysis to ASA classes IV–V alone, the inclusion criterion later used in the B-Unaware trial, it is unclear whether high ASA class would still have been identified as an independent risk factor for awareness. Uncertainty on this issue is compounded by Domino and colleagues'13 review of closed claims relating to awareness, in which no significant association between ASA class and awareness risk was found. As for marginal exercise tolerance, I can find no evidence for this being independently associated with a high risk of awareness.
Use of these new, weaker criteria in the B-Unaware trial is likely to have reduced the overall incidence of awareness from the 1% seen in the B-Aware trial to a lower figure, quite possibly identical to the one actually seen. In other words, the observed incidence of 0.21% may not represent a reduction, consequent on anaesthetic technique, from some hypothetical baseline but merely the effect of choosing patients with different characteristics.
Leaving aside whether the two B-Unaware strategies have any effect on awareness at all, Sneyd and Mathews further conclude that the incidence of awareness in the two groups is the same. This is incorrect. The study's a priori power calculations were based on an anticipated 1% incidence of awareness in the ETAG group and 0.1% for the BIS group. With these figures, a total of 940 patients are required in each group to detect a 0.9% difference with a one-tailed alpha of 0.05 and a power of 80%. Online statistical software14 conveniently allows both reproduction of the original calculation and recalculation using the actual, rather than the predicted, incidence of awareness. This indicates that to detect a between-group difference in awareness proportional to the one the investigators sought (i.e. from 0.21% to 0.021%), the B-Unaware sample size would have provided just 4% power.
The adequately powered B-Aware study established that BIS-guided anaesthesia reduces the incidence of intraoperative awareness in patients genuinely at risk from this complication. The inadvertently underpowered B-Unaware study gives few grounds to doubt this finding, or to assert the equivalence with BIS monitoring of any anaesthesia delivery protocol. Whether we are inclined to B-Aware or to B-Unaware, careful examination of the evidence is always advisable lest our conclusions B-Unjustified.
Plymouth, UK
* E-mail: robert.sneyd{at}pms.ac.uk
Editor—I am grateful for the interest and comments on the published Abstracts from the recent Memory and Awareness, MAA7 meeting,2 and the accompanying editorial.1
Dr Ponte is right to be concerned about the lack of attention to the possible role of neuromuscular blockers in awareness. A recent study from Spain described an incidence of awareness of 1%, and all 39 patients with conscious awareness had received neuromuscular blocking agents.15 However, it is probably more appropriate to take issue with the research community rather than with those writing editorials—we can only report that which we see and hear. In fact, the MAA7 meeting did again contain mention of the isolated forearm technique. It remains likely that a proportion of cases of awareness could be avoided by the general adoption of relaxant-free techniques.
Regarding nitrous oxide, Drs Lynch and Grant have themselves pointed out the incidence of awareness in patients randomized to nitrous oxide in the ENIGMA5 study, so the lack of nitrous oxide in the patients with awareness in the B-Unaware study4 may simply be a coincidence. The key issue is the lack of data. How different MAC fractions of inhalation agents and nitrous oxide do or do not combine to prevent awareness remains unclear. Only a study with patients randomized to equi-MAC anaesthetics with and without nitrous oxide can definitively resolve this.
Dr Morley takes the issue with the assumed awareness risk of 1% in high-risk patients—this was proposed by the B-Unaware authors4 on the basis of three published studies. The B-Unaware study comprised two intervention groups [BIS-guided anaesthesia and a protocol based on a measurement of end-tidal anaesthetic gases (ETAG) anaesthesia]. In the absence of any ‘standard anaesthesia’ group, we can only speculate about what the baseline risk of awareness might have been. Perhaps 1% if we accept that the patients were indeed ‘high risk’—or perhaps less if we accept Dr Morely's critique of the inclusion criteria. Since we do not know what the baseline risk was, it is indeed true that both BIS and ETAG may be either very effective or entirely ineffective, but crucially, they were equally so. It is also important to recognize that if the baseline incidence of awareness is low, that is, nearer 0.2% than 1%, then the B-Unaware study was underpowered to resolve the differences between the two techniques. This does not make BIS a better technique than ETAG—it just leaves us uncertain.
References
1 Sneyd JR, Mathews DM. Memory and awareness during anaesthesia. Br J Anaesth (2008) 100:742–4.
2 Proceedings of the 7th International Symposium Memory and Awareness in Anaesthesia. Br J Anaesth (2008) 100:868–80.
3 Ponte J. Neuromuscular blockers during general anaesthesia: less may be better. Br Med J (1995) 310:1218–9.
4 Avidan MS, Zhang L, Burnside BA, et al. Anesthesia awareness and the bispectral index. N Engl J Med (2008) 358:1097–108.
5 Myles PS, Leslie K, Chan MT, et al. Avoidance of nitrous oxide for patients undergoing major surgery: a randomized controlled trial. Anesthesiology (2007) 107:221–31.[CrossRef][Web of Science][Medline]
6 Orser BA. Depth-of-anesthesia monitor and the frequency of intraoperative awareness. N Engl J Med (2008) 358:1189–91.
7 Sebel PS, Bowdle TA, Ghoneim MM, et al. The incidence of awareness during anesthesia: a multicenter United States study. Anesth Analg (2004) 99:833–9.
8 Sandin RH, Enlund G, Samuelsson P, Lennmarken C. Awareness during anaesthesia: a prospective case study. Lancet (2000) 355:707–11.[CrossRef][Web of Science][Medline]
9 Ranta S, Jussila J, Hynynen M. Recall of awareness during cardiac anaesthesia: influence of feedback information to the anaesthesiologist. Acta Anaesthesiol Scand (1996) 40:554–60.[Web of Science][Medline]
10 Phillips AA, McLean RF, Devitt JH, Harrington EM. Recall of intraoperative events after general anaesthesia and cardiopulmonary bypass. Can J Anaesth (1993) 40:922–6.[Web of Science][Medline]
11 Myles PS, Leslie K, McNeil J, Forbes A, Chan MT. Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware randomised controlled trial. Lancet (2004) 363:1757–63.[CrossRef][Web of Science][Medline]
12 Fassoulaki A, Farinotti R, Servin F, Desmonts JM. Chronic alcoholism increases the induction dose of propofol in humans. Anesth Analg (1993) 77:553–6.
13 Domino KB, Posner KL, Caplan RA, Cheney FW. Awareness during anesthesia: a closed claims analysis. Anesthesiology (1999) 90:1053–61.[CrossRef][Web of Science][Medline]
14 Available from http://hedwig.mgh.harvard.edu/sample_size/fisher/fishapp.html. Accessed June 9, 2008.
15 Errando CL, Sigl JC, Robles M, et al. Awareness with recall during general anaesthesia: a prospective observational evaluation of 4001 patients. Br J Anaesth (2008) 101:178–85.
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